ADH1C maintains the homeostasis of metabolic microenvironment to inhibit steatotic hepatocellular carcinoma

Steatotic hepatocellular carcinoma (HCC) has emerged as a significant subtype of HCC. Understanding the complex tumor microenvironment in HCC is particularly important for stratifying patients and improving treatment response. In this study, we performed proteomic analysis on clinical samples of steatotic HCC and identified human-specific gene alcohol dehydrogenase 1C (ADH1C) as a key factor. ADH1C is a favorable prognostic factor in both steatotic and non-steatotic HCC. ADH1C promotes fatty acid degradation through a novel non-enzymatic function, inhibiting the development of hepatocellular carcinoma. Specifically, in vitro experiments revealed that ADH1C interacts with splicing factor retinitis pigmentosa 9 (RP9) to enhance the splicing of key transcription factor peroxisome proliferator activated receptor alpha (PPARa) pre-mRNA, which is crucial for fatty acid degradation. The regulation of the ADH1C/RP9/PPARa axis was supported by in vivo experiments and clinical relevance. This leads to a reduction in the critical metabolite palmitic acid, subsequently decreasing the palmitoylation levels of oncogenic protein TEA domain transcription factor 1 (TEAD1), thereby regulating the hippo pathway and subsequent cell proliferation inhibition. Additionally, we found that ADH1C and PPARa can serve as combined biomarkers to distinguish between patients with steatotic and non-steatotic HCC. Combination therapy targeting ADH1C and anti-programmed cell death protein 1 (PD1) enhances the response of steatotic HCC to anti- PD1 immunotherapy. Our study revealed a central role of ADH1C/PPARa in lipid metabolism and HCC suppression. Targeting lipid metabolism via ADH1C/PPARa may provide new therapeutic strategies for the treatment of liver cancer.